Antipsychoic 4-(4-(3-benzisothiazolyl)-1-piperazinyl)buytl bridged bicycle imides

ABSTRACT

4-(4-(3-Benzisothiazolyl)-1-piperazinyl)butyl bridged bicyclic imides of formula (I) and their pharmaceutically acceptable acid addn. salts are new: R1R2=H, Me, Et X=-CH2-, -CH2CH2-, -CH2CH2CH2- Y = CR3R4 R3, R4 = H, Me .

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to bridged bicyclic imides substituted on thenitrogen thereof with the 4-[4-(3-benzisothiazolyl)-1-piperazinyl]butylgroup and their use as antipsychotics.

A variety of antipsychotic agents are known to date. These includetricyclic compounds such as chlorpromazine(2-chloro-N,N-dimethyl-10H-phenothiazine-10-propenamine); butyrophenonecompounds such as haloperidol(4-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]-1-(4-fluorophenyl)-1-butanone);and certain spiroimide compounds such as busprione(8-[4-(2-pyrimidinyl)-1-piperazinylbutyl]-8-azaspiro[4,5]decane-7,9-dione)and tiaspirone (8-[4-(3-benzisothiazolyl)-1-piperazinylbutyl]-8-azaspiro[4,5]decane-7,9-dione). More recently, antipsychoticsin which the azaspiro group is replaced by a fused bicyclic imide groupand which allegedly exhibit fewer extra pyramidal side effects thanpreviously described antipsychotics have been reported (see below).However, there remains a need for anti-psychotic agents which exhibitselectivity of action.

2. Description of the Prior Art

Certain glutarimide and succinimide compounds, substituted on nitrogenby a (4-aryl-1-piperazinyl)alkyl or (4-heteroaryl-1-piperazinyl)alkylgroup, and having tranquillizing, antianxiety and/or anti-emeticproperties are known from U.S. Pat. Nos. 3,717,634 and 3,907,801;4,411,901 and 4,452,799; 4,182,763; 4,423,049; 4,507,303 and 4,543,355;4,562,255; and EP-196,096. Korgaonka et al., J. Indian Chem. Soc., 60874 (1983), disclose a number of N-(3-[4-aryl-1-piperazinyl]propyl)-camphorimides, which are alleged to have sedative properties in mice.

The most pertinent compounds of the above references have the generalformula: ##STR1## wherein the values of A and B are: U.S. Pat. No.3,717,634 ##STR2## and U.S. Pat. No. 3,907,901: ##STR3## U.S. Pat. No.4,182,673: ##STR4## U.S. Pat. No. 4,423,049: ##STR5## U.S. Pat. No.4,411,901 ##STR6## and U.S. Pat. No. 4,452,799: ##STR7## U.S. Pat. No.4,507,303 ##STR8## and U.S. Pat. No. 4,543,355; ##STR9## and U.S. Pat.No. 4,562,255:

U.S. Pat. No. 4,745,117: ##STR10## and EP 0196096 ##STR11##

SUMMARY OF THE INVENTION

The compounds of this invention have the formula (I) ##STR12## and thepharmaceutically-acceptable acid addition salts thereof, wherein X is--CH₂ --, --CH₂ CH₂ -- or --CH₂ CH₂ CH₂ --; and

Y is CR³ R⁴ wherein each of R³ and R⁴, which may be alike or different,is hydrogen or methyl; and

each of R¹ and R², which may be alike or different, is hydrogen, methylor ethyl.

The present invention also relates to pharmaceutical compositionscomprising a compound of formula (I) or a pharmaceutically-acceptableacid addition salt thereof and a pharmaceutically-acceptable carrier ordiluent and to the use of formula (I) compounds or a pharmaceuticalcomposition thereof for the treatment of a psychotic disorder in a humanbeing suffering therefrom.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of formula (I) are conveniently prepared by reactingN-(3-benzisothiazolyl)piperazine with a compound of formula (II)##STR13## wherein Z is halo (especially chloro, bromo, iodo) or otherreadily displaced (leaving) group such as tosyloxy or mesyloxy. Thereaction is carried out in a reaction-inert solvent (i.e., one in whichat least one of the reactants is partially soluble and which does notadversely interact with reactants or product), generally at or near thereflux temperature of said solvent until substantially complete. Thereaction temperature may range from 50° C. to about 200° C. In general,however, temperatures of from about 50° C. to 150° C. are adequate. Thetime required for substantially complete reaction is, of course,dependent upon the reaction temperature and the value of Z in theformula (II) reactant. A favored solvent, especially when Z in theformula (II) is tosyloxy is methyl isobutyl ketone. Other suitable, andtypical, reaction-inert solvents are hydrocarbons such as benzene,toluene, xylene and decalin; the methyl and ethyl ethers of ethyleneglycol, propylene glycol and diethylene glycol; and cyclic ethers suchas tetrahydrofuran; acetonitrile.

The reaction is conducted in the presence of an inorganic or organicacid acceptor, representative of which are alkali and alkaline earthcarbonates, bicarbonates or hydrides; or a tertiary amine. The preferredacid acceptors are sodium or potassium carbonate. Satisfactory yields ofproduct are realized with reaction periods ranging from about 2-100hours. The product is recovered by known methods such as extraction.Purification is accomplished by conventional methods such aschromatography on silica gel using chloroform/methanol or ethanol aseluant; or by crystallization techniques of the formula (I) compound oran acid addition salt thereof.

Other methods of preparing formula (I) compounds will be apparent tothose skilled in the art.

The formula (II) reactants are prepared by reacting the appropriateanhydride, e.g., d-camphoric anhydride, with 4-hydroxybutylamine. Thisreaction is carried out by heating under substantially anhydrousconditions, substantially equimolar quantities of the two compounds at atemperature from 90° to 160° C., until the reaction is substantiallycomplete. The two reactants are usually heated in a reaction-inertsolvent; however, in those cases in which one or both of the reactantsis molten at the reaction temperature, the two reactants can be heatedin the absence of solvent. A reaction-inert solvent is one in which atleast one of the reactants is soluble, and which does not adverselyinteract with either of the starting reactants or the product of theformula (I). Typical reaction-inert solvents which can be used includehydrocarbons such as benzene, toluene, xylene and decalin; the methyland ethyl ethers of ethylene glycol, propylene glycol and diethyleneglycol; and acetonitrile.

The product is recovered by standard procedures such as concentration ofthe reaction mixture.

The thus-obtained 4-hydroxybutyl substituted cyclic imide is thenconverted to a compound of formula (II). Preferred formula (II)compounds are those wherein Z is tosyloxy. Said compounds are obtainedby reaction of the 4-hydroxybutyl substituted cyclic imide with anexcess, e.g., 10%, of tosyl chloride in the presence of an acidacceptor, preferably sodium or potassium carbonate, in pyridine. Thereaction is generally initially started at a temperature of about 0°-10°C. for one to two hours, after which it is allowed to rise to ambienttemperature. Following a total reaction period of 4-6 hours, thetosyloxy derivative is recovered by extraction.

Acid-addition salts of a compound of the formula (I) are prepared byconventional methods. In a typical procedure, a compound of formula (I)is combined with a stoichiometric amount of an appropriate acid in aninert solvent, which can be aqueous, partially aqueous or non-aqueous.The salt is then recovered by solvent evaporation, by filtration if thesalt precipitates spontaneously, or by precipitation using a non-solventfollowed by filtration. Typical salts which can be prepared includesulfate, hydrochloride, hydrobromide, nitrate, phosphate, citrate,tartrate, pamoate, sulfosalicylate, methanesulfonate, benzenesulfonateand 4-toluenesulfonate salts.

The antipsychotic activity of compounds of formula (I) is demonstratedby various assay methods known to those skilled in the art. One of themore significant assays is the dopamine binding assay [Burt et al.,Molec. Pharmacol. 12, 800 (1976); Creese et al., Science 192, 481(1976)]. A further procedure of value in demonstrating theirantipsychotic activity is the apomorphine stereotypy test [Janssen etal., Arzneimittel Forsch. 17, 841 (1966)]. Based upon these procedures,formula (I) compounds are found to exhibit potent inhibition of dopaminebinding in the rat brain and to reverse apomorphine-induced stereotypyin rats.

A compound of formula (I), or a pharmaceutically-acceptable saltthereof, can be administered to a human subject either alone, or,preferably, in combination with pharmaceutically-acceptable carriers ordiluents, in a pharmaceutical composition according to standardpharmaceutical practice. A compound can be administered orally orparenterally, which includes intravenous and intramuscularadministration. However, the preferred route of administration is oral.Additionally, in a pharmaceutical composition comprising a compound offormula (I), or a pharmaceutically-acceptable salt thereof, the weightratio of carrier to active ingredient will normally be in the range from20:1 to 1:1, and preferably 10:1 to 1:1. However, in any given case, theratio chosen will depend on such factors as the solubility of the activecomponent, the dosage contemplated, and the precise dosage regimen.

For oral use of a compound of this invention, the compound can beadministered, for example, in the form of tablets or capsules, or as anaqueous solution or suspension. In the case of tablets for oral use,carriers which can be used include lactose and corn starch, andlubricating agents, such as magnesium stearate, can be added. For oraladministration in capsule form, useful diluents are lactose and driedcorn starch. When aqueous suspensions are required for oral use, theactive ingredient can be combined with emulsifying and suspendingagents. If desired, certain sweetening and/or flavoring agents can beadded. For intramuscular and intravenous use, sterile solutions of theactive ingredient can be prepared, and the pH of the solutions should besuitably adjusted and buffered. For intravenous use, the totalconcentration of solutes should be controlled to render the preparationisotonic.

When a compound of the present invention is to be used in a humansubject, the daily dosage will be determined by the prescribingphysician. In general, the dosage will depend on the age, weight andresponse of the individual patient, as well as the severity of thepatient's symptoms. However, in most instances, an effective amount of acompound of the formula (I), or a pharmaceutically-acceptableacid-addition salt thereof, will be from 1 to 300 mg per day, andpreferably 5 to 100 mg per day, in single or divided doses. Naturally,the more active compounds of the invention will be used at the lowerdoses, while the less active compounds will be used at the higher doses.

The following examples and preparations are being provided solely forfurther illustration. For nuclear magnetic resonance spectra (NMRspectra), absorptions are given in parts per million (ppm) downfieldfrom tetramethylsilane.

EXAMPLE 13-(4-[4-(3-Benzisothiazolyl)-1-piperazinyl]butyl)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane-2,4-dioneA.3-(4-Hydroxybutyl)-1,8,8-trimethyl-3-azabicyclo-[3.2.1]octane-2,4-dione

To a 125 ml round-bottomed flask equipped with Dean-Stark trap,condenser, and N₂ inlet were added 5.35 g (29 mmol) of d-camphoricanhydride, 2.49 g (28 mmol) of 4-hydroxybutylamine, and 60 ml oftoluene. The reaction was refluxed with separation of water for 20hours. It was then cooled, concentrated to an oil, and the oil dissolvedin ethyl acetate. The ethyl acetate solution was washed with 5% HCl, 5%NaOH, and brine, dried over sodium sulfate, and evaporated to an oil,6.0 g (85%).

NMR (delta, CDCl₃): 0.87 (two s, 6H), 1.11 (s, 3H), 1.3-1.5 (m, 2H),1.65-1.95 (m, 2H), 2.54 (s, 1H), 3.3-3.7 (m, 4H).

MS (%): 254 (18), 253 (18, parent), 236 (23), 235 (37), 226 (17), 223(47), 222 (23), 220 (21), 209 (13), 208 (14), 206 (29), 195 (33), 194(100), 182 (76), 181 (22), 166 (24), 138 (31), 137 (31), 136 (15), 124(17), 123 (18), 112 (35), 111 (15), 110 (28), 109 (86), 108 (10), 105(12), 98 (27), 97 (12), 96 (34), 95 (55), 93 (11), 91 (14).

B3-(4-Tosyloxybutyl)-1,8,8-trimethyl-3-azabicyclo-[3.2.1]octane-2,4-dione

To a 250 ml round-bottomed flask equipped with N₂ inlet were added 5.35g (21.1 mmol) of3-(4-hydroxybutyl-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane-2,4-dione,4.43 g (23.3 mmol) of tosyl chloride, 5.84 g (42.2 mmol) of potassiumcarbonate, and 70 ml of pyridine. The reaction was initially stirred at0° C., then stirred at room temperature for 5 hours. It was then pouredinto water and extracted into methylene chloride. The organic layer wassubsequently washed with water, copper sulfate solution, sodiumcarbonate solution, water, and brine, dried over sodium sulfate, andevaporated to an oil, 5.3 g (62%).

NMR (delta, CDCl₃): 0.87 (two s, 6H), 1.11 (s, 3H), 1.3-1.5 (m, 2H),1.65-1.95 (m, 2H), 2.42 (s, 3H), 3.5-3.7 (m, 2H), 3.9-4.1 (m, 2H),7.2-7.8 (m, 4H).

MS (%): 409 (10), 408 (31), 407 (11, parent), 252 (21), 237 (24), 236(100), 235 (88), 226 (10), 220 (20), 207 (44), 206 (81), 194 (40), 182(12), 173 (10), 166 (14), 155 (20), 138 (11), 137 (14), 136 (11), 112(11), 110 (13), 109 (49), 108 (12), 107 (11), 96 (14), 95 (37), 93 (12),91 (81).

C.3-(4-[4-(3-Benzisothiazolyl)-1-piperazinyl]butyl)-1,8,8-trimethyl-3-azabicyclo-[3.2.1]octane-2,4-dioneHydrochloride

To a 125 ml round-bottomed flask equipped with condenser and N₂ inletwere added 0.5 g (1.95 mmol) of N-(3-benzisothiazolyl)-piperazine(prepared according to U.S. Pat. No. 4,452,799), 0.8 g (1.95 mmol) of3-(4-tosyloxybutyl)-1,8,8-trimethyl-3-azabicyclo[3.2.1]-octane-2,4-dione,0.42 g (3.91 mmol) of sodium carbonate, and 50 ml ofmethylisobutylketone. The reaction was refluxed 4 days, cooled, andevaporated. The oil was taken up in ethyl acetate, washed with water andbrine, dried over sodium sulfate, and evaporated to an oil. The oil wasdissolved in ether, treated with ether saturated with HCl, and theprecipitate collected under N₂ and dried to a hygroscopic, tan solid,210 mg (22%).

NMR (delta, DMSO-d₆): 0.88 (s, 3H), 0.92 (s, 3H), 1.11 (s, 3H), 1.4-1.5(m, 2H), 1.6-1.8 (m, 2H), 1.8-2.0 (m, 2H), 2.1-2.3 (m, 1H), 2.7 (m, 1H),3.1-3.7 (m, 10H), 4.0-4.1 (m, 2H), 7.4-7.7 (m, 2H), 8.1-8.2 (m, 2H). IR(cm⁻¹, DMSO): 1724 and 1664 (C=0).

MS (%): 454 (20), 439 (10), 319 (13), 318 (46), 305 (11), 304 (20), 292(16), 291 (62), 280 (13), 279 (64), 277 (12), 236 (16), 232 (55), 203(16), 194 (11), 190 (12), 189 (16), 179 (11), 178 (11), 177 (65), 176(44), 175 (13), 166 (12), 164 (13), 163 (74), 162 (15), 151 (23), 150(15), 149 (17), 137 (30), 136 (22), 135 (69), 134 (24), 125 (20), 124(19), 123 (96), 120 (15), 112 (19), 111 (64), 110 (36), 109 (100), 108(20), 107 (11), 105 (11).

EXAMPLE 2

In like manner the following compounds of formula (I) are preparedaccording to the procedure of Example 1 but using the appropriatebicyclic anhydride in place of d-camphoric anhydride:

    ______________________________________                                         ##STR14##                                                                    R.sup.1                                                                              R.sup.2        X       Y                                               ______________________________________                                        H      H              CH.sub.2                                                                              CH.sub.2                                        H      H              (CH.sub.2).sub.2                                                                      CH.sub.2                                        H      H              (CH.sub.2).sub.3                                                                      CH.sub.2                                        H      H              (CH.sub.2).sub.2                                                                      (CH.sub.2).sub.2                                H      H              CH.sub.2                                                                              C(CH.sub.3).sub.2                               H      H              (CH.sub.2).sub.2                                                                      C(CH.sub.3).sub.2                               CH.sub.3                                                                             CH.sub.3       (CH.sub.2).sub.2                                                                      CH.sub.2                                        CH.sub.3                                                                             CH.sub.2 CH.sub.3                                                                            (CH.sub.2).sub.2                                                                      CH.sub.2                                        ______________________________________                                    

We claim:
 1. A compound of the formula (I) ##STR15## or apharmaceutically-acceptable acid addition salt thereof, wherein each ofR¹ and R², which may be alike or different, is hydrogen, methyl orethyl;X is --CH₂ --, --CH₂ CH₂ -- or --CH₂ CH₂ CH₂ --; and Y is (CH₂)₂ -or CR³ R⁴ wherein each of R³ and R⁴, which may be alike or different, ishydrogen or methyl.
 2. A compound according to claim 1 wherein each ofR¹ and R² is hydrogen; Y is CH₂ and X is --CH₂ --.
 3. A compoundaccording to claim 1 wherein R¹ is methyl; R² is hydrogen; Y is CH₂ ;and X is CH₂ CH₂ --.
 4. The compound according to claim 1 wherein R¹ ismethyl; R² is hydrogen; Y is C(CH₃)₂ and X is --CH₂ CH₂ --.
 5. A methodof treating psychosis in a subject in need of such treatment whichcomprises administering to said subject an antipsychotic effectiveamount of a compound according to claim
 1. 6. A pharmaceuticalcomposition having antipsychotic activity comprising an antipsychoticeffective amount of a compound according to claim 1, and apharmaceutically-acceptable carrier.